Despite much progress that has been made during past decades, current approaches in tumor immunotherapy remain less successful than desired. One major obstacle that prevents development of effective anti-tumor immunity is that most tumor cells lack the co-stimulatory signals essential for T cell activation and are protected by the suppressive cytokines such as TGF-beta. Recent studies by us and others have identified that CD8+ T cells ablated Cbl-b, a member of ubiquitin E3 ligase family, may overcome such an obstacle and thus provide a novel target for eliciting effective anti-tumor immunity against a broad spectrum of cancers. In this proposal, we present a plan to generate a modified version of nanoparticle to specifically silence Cbl-b in mouse and human CD8+ T cells. This nanoparticle system conjugated with single chain CD8 antibody is anticipated to deliver siRNA specifically to CD8+ T cells and facilitate siRNA release into the cytosol. We propose to use the improved nanoparticles to determine whether this targeted siRNA delivery system can silence Cbl-b in mouse or human CD8+ T cells in wild type mice or hu-SCID mice reconstituted with human PBMCs. We expect that availability of such vehicles will set up a solid foundation to proceed to next stage of study to test the multifunctional nanoparticle-based strategy in cancer therapy using mouse tumor models and in human clinical trials.